Finding new insights into cancer metastasis: Linking cell migration to metabolic energy flux

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The vast majority of deaths due to cancer are caused by recurrence or spread around the body, termed as metastasis. Surgery and chemotherapy can often be used to remove a primary tumour, but if cancer spreads to other parts of the body, treatment options are more limited. Cells move out of the primary tumour when nutrients are scarce and this is how they spread around the body. Pancreatic cancer is one of the worst types of cancer for metastasis and recurrence and only limited treatments are currently available. Our aim is to use pancreatic cancer cells to discover new ways to target this disease and stop it spreading.Tumours typically grow rapidly and consume a large amount of energy to fuel this growth. Consequently, tumour cells have adapted ways to produce more energy and obtain alternative food sources to normal cells. To identify metabolic regulators that were tightly coupled with cell shape and cytoskeletal organisation, we performed a high content imaging based siRNA screen against 494 genes known to be metabolic regulators. Two mouse KPC PDAC cell lines (A and B, both KRasG12D and p53R172H) were independently screened to maximise reliability. We identified the top 10% of hits consistent between the two cell lines showing abnormal shape and impaired in migration but not growth rate, suggesting multiple pathways connecting migration and metabolism. Our screen has uncovered two main functional categories connecting migration to metabolism- mitochondrial (OXPHOS) related (Group 1) or glycolytic related (Group 2).In this project, we will focu on those two main classes of hits and perform cell biological analysis on the candidates to determine the mechanisms by which they affect energy production/consumption and cell migration. Our experiments will focus on how cells couple energy production and nutrient uptake with migration and invasion. Our goal is to identify 1-2 key pathways connecting these processes that could be targetted in vivo in the future to develop new therapeutic angles against pancreatic ductal adenocarcinoma. The outcomes that we expect from this project include:Uncovering key molecular pathways regulating the coupling between mitochondrial energy production and cell migration and invasion.Developing a coherent model for how the actin cytoskeleton scaffolds the vacuolar V-ATPase and glycolytic enzymes to regulate the pH balance when cells are glycolytic.Understanding how integrin trafficking couples with V-ATPase trafficking to regulate tumour cell invasion and maintenence of pH homeostasis by mechanosensing.Modeling how these genes affect invasion into a reconstituted tumour environment, simulating the process of cancer cells migrating out from the primary tumour.Determination of which key aspects of cell migration regulate energy production and consumption so that these can be therapeutically targetted, first for pancreatic cancer, and then for other cancers that also spread through metastasis.